It has long been appreciated that multiple injections of certain antigens are required to elicit an adequate immune response and production of antibodies [1]. A suitable and widely used method is the sub-dermal or subcutaneous injection of antigen together with one or more adjuvants in liquid formulations by needle. However, the necessity for such multiple injections has greatly increased the cost and inconvenience of immunization programes both in human and veterinary medicine. Furthermore, in third world countries, not only has the need for such multiple injections meant that many human patients receive an incomplete course of immunisation, but conditions are often such that liquid formulations for injections are subject to adverse storage conditions, or made up under non-sterile conditions.
In veterinary and human medicine there is therefore a need for dosage forms which after a single administration result in the release of antigen at different times [5,7]. The release may be continuous or occur as one or more pulses delayed for a period of time after administration. Such a delayed release implant has considerable potential in veterinary medicine as it allows two or more doses of antigen to be administered in a single handling of the animal, resulting in significant cost saving. The use of such a delivery system in human medicine in third world countries would also contribute significantly to savings in utilization of scarce medical resources, as co-administration of immediate and delayed release implants permits a second pulse of antigen to be released a set time period after implantation. This ensures that the booster dose of antigen is received, which in many vaccines is essential to achieve appropriate efficacy.
Small, usually cylindrically shaped implants, which are inserted into the subcutaneous tissue using a specially designed implanter, have been widely used as controlled release delivery systems in veterinary medicine (2,3). The polymers and excipients used in such devices must be biocompatible (2) and or biodegradable (2,16,17). Applications suggested for veterinary controlled release devices include disease prevention, growth promotion, vaccination, fertility control, and supplementation of nutritional agents (4,5). Recently, Caster, Luttinger and Gardner [4] have reviewed the use of controlled release parenteral systems for veterinary use and tabulate commercially available products and delivery systems under development. In humans, subcutaneous delivery systems based on Silicone tube implants have been used to deliver steroids and anti-inflammatory drugs (6). Modulated and triggered drug delivery systems which use pH sensitive polymers in subdermal devices are being developed (19).
In the application of an implant for antigen delivery (vaccination) it may be preferable to release antigen as a pulse rather than continuously over a period of time. Pulsed release mimics most closely the administration of liquid injections at set time intervals [1], which is the current regimen used to obtain protection from disease. Some pulsed systems for oral delivery have been described in which the dose is divided, the second portion being released some hours after administration [10], or alternatively comprising a number of pellets which can rupture at controlled times over a twelve hour period [11].
Australian Patent No. 601443 (WO-87/06828) describes an implant which releases a peptide or protein in a substantially continuous manner at a substantially constant rate over a desired period, without any significant delay phase. The implant comprises a permeable, non-dissolving polymeric coating which forms a release rate limiting barrier, and which does not degrade over the life of the implant
International Patent Application No. WO 91/04052 describes a solid vaccine composition containing an antigenic substance, saponin, and a polycationic adjuvant, which may be formulated as an implant in which pulsed release may be achieved by coating the vaccine with different thicknesses of polymer.
International Patent Application No. WO 87/06129 describes an implant formulation in which controlled release of active agent is achieved by using a plurality of biodegradable microcapsules within a biodegradable polymeric implant. An optional coating may be provided for impact resistance; this coating is biodegradable at a more rapid rate than the biodegradable micro capsules.
International Patent Application No. WO 91/0713 describes an oral contraceptive dosage form providing a pulsed dose of oestrogen and progesterone via immediate release of an outer, biodegradable coat on an implant, followed by delayed release of oestrogen via an osmotic device consisting of two compartments, of which the second compartment contains salt and has osmotic swelling properties, which force the active agent out through a pore in the outer coat. None of these three specifications discloses the combination of water soluble and water insoluble excipients, and in particular a water insoluble, swellable excipient is not disclosed.
A microencapsulated liposome system for vaccine delivery is described by Cohen, Chow and Langer [12]. Delayed pulsed release of FITC-BSA is achieved using the delivery system. However, there is a continuous release at low levels between the two pulses; the delayed pulse occurs some 17-95 days after the initial release of FITC-BSA. U.S. Pat. No. 4,900,556 describes biologically active agents entrapped in liposomes which are protected from the biological environment by microencapsulation.
We have now designed delayed pulsed release implants which satisfy the above requirements, at least in part, and which can be prepared using readily available pharmaceutical excipients and techniques already used in the known prior art of tabletting and film coating. This specification describes implants which are designed to give a delayed pulsed release. When implanted in conjunction with an immediate release implant (or alternatively a conventional liquid injection) the combination is capable of releasing an initial pulse of antigen, then a second antigen pulse typically 10-60 days after implantation (delayed release). For many applications the preferred time is 20-60 days.